JP2002519412A - Potassium channel blocker - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel potassium channel blockers and their use in the manufacture of pharmaceutical formulations. Furthermore, the present invention relates to diseases or disorders related to the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary convulsions, kidney disorders, polycystic kidney disease, Bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, intracerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury , Mental illness, anxiety, depression, dementia, memory and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, apsans seizures, myotonic muscular dystrophy, Pharmaceutical compositions useful for treating or reducing xerostomia, diabetes type II, hyperinsulinemia, preterm birth, baldness, cancer and immunosuppression.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a novel potassium channel blocker and a method of using the same for preparing a pharmaceutical composition.

Furthermore, the present invention relates to diseases or disorders related to the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary convulsions, renal impairment, renal dysfunction Cystic disease, bladder spasm, urinary incontinence, bladder outflow obstruction,
Irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury, mental illness, anxiety, depression, dementia , Memory and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, apsans seizure, myotonic muscular dystrophy, xerostomia, diabetes type II, high insulin Pharmaceutical compositions useful for the treatment or alleviation of blood, premature birth, baldness, cancer and immunosuppression.

BACKGROUND Ion channels are transmembrane proteins that catalyze the transport of inorganic ions across cell membranes. Ion channels are involved in various processes as well as the development and timing of action potentials, synaptic transmission, secretion of hormones, muscle contractions, and the like.

[0004] All mammalian cells generate potassium (K ⁺ ) channels in their cell membranes, which play a dominant role in regulating membrane potential. In nerve and muscle cells, they regulate the generation of frequency and action potentials, the release of neurotransmitters, and the degree of broncho- and vasodilation.

From a molecular point of view, this K ⁺ channel represents the largest and most diverse group of ion channels. In summary, they can be divided into five large subfamilies: voltage-activated K ⁺ channel (K _v ), long Q
T-associated K ⁺ channel (kvLQT), inner rectifier (K _IR ), two-pore K ⁺ channel (K _TP ) and calcium-activated K ⁺ channel (K _ca ).

The latter group, Ca ²⁺ -activated K ⁺ channels, consists of three distinct subtypes: SK channels, IK channels and BK channels. S
K, IK and BK represents a single-channel conductance (S mall, I ntermadiateand B igconductance K channel). The SK, IK and BK channels show differences, for example, in voltage- and calcium-sensitivity, pharmacology, distribution and function.

SK channels are present in many central nervous systems and ganglia, where this first effect is to prevent long continuous epilepsy-inducing activity from taking place in neurons with one or several action potentials Is excessively polarized. SK channels are also present in several peripheral cells, including skeletal muscle, gland cells, hepatocytes, and T-lymphocytes. The significance of SK channels in normal skeletal muscle is not clear, but their number is significantly increased in denervated muscle, and a large number of SK channels in muscle of patients with myotonic dystrophy are involved in the development of the disease. Suggest a role.

[0008] K ⁺ channels are associated with many diseases, especially asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary artery convulsions, renal impairment, polycystic kidney disease,
Bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, intracerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury , Mental illness, anxiety, depression, dementia, memory and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, apsans seizures, myotonic muscular dystrophy, Various studies have shown therapeutic goals in the treatment of xerostomia, diabetes type II, hyperinsulinemia, preterm birth, baldness, cancer and immunosuppression.

[0009] Many neuromuscular blocking agents having effects on SK channels include, for example, apamin,
Present as atracurium, pancuronium and tubocurarine.

[0010] International Patent Application Publication No. WO 97/48705 describes that certain groups of compounds are useful as calcium-activated potassium channel blockers. However, no selectivity for the SK channel is disclosed.

US Pat. Nos. 5,739,127 and 5,760,230 describe another group of compounds that act on potassium channels.

SUMMARY OF THE INVENTION The present invention is to provide novel compounds that can selectively block SK channels or subtypes of SK channels.

Furthermore, the present invention relates to diseases or disorders related to the activity of potassium channels, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary convulsions, renal disorders, renal dysfunction. Cystic disease, bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease,
Angina, coronary heart disease, traumatic brain injury, mental illness, anxiety, depression, dementia,
Memory and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Lenneau's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, apsans seizures, myotonic muscular dystrophy, xerostomia, diabetes type II, hyperinsulinemia Pharmaceutical compositions useful for the treatment or alleviation of disease, premature birth, baldness, cancer and immunosuppression.

Therefore, according to this first aspect, the present invention provides a novel compound selected from the group represented by the following general formulas I to VIII.

According to another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention.

According to another aspect, a method of using a compound of the invention for the manufacture of a medicament for the treatment or alleviation of a disease or disorder associated with potassium channel activity, and a disorder or condition responsive to potassium channel blockade Or a method for alleviating the above.

DETAILED DESCRIPTION OF THE INVENTION Potassium Channel Blocker According to this first aspect, the present invention provides novel compounds. The compounds of the present invention are particularly useful as potassium channel blockers.

Accordingly, the present invention provides a potassium channel blocker, particularly an SK channel blocker, selected from the group represented by the following general formulas I to VIII.

Formula I

[0020]

Embedded image Wherein A is a spacing group having 1-20 atoms, a space group having a chain length of 1-20 atoms, or 1-20 separate bonds.
And a space group having a chain length of A bis (aminobenzimidazole) derivative represented by the formula:

[0021] The space group A is preferably a linear or branched alkylene chain having from 1 to 15 carbon atoms. The alkylene group is represented by one or more oxygen or sulfur atoms or of the formula -NR'- or = NR '(wherein, R' represents hydrogen or alkyl)
Embedded image which may be interrupted by one or more residues represented by the formula: or — (CH ₂ ) _a -D— (CH ₂ ) _b — wherein a and b may be the same or different, and represents a number of 0, 1, 2, 3, 4, or 5, and D represents a carbon atom of 6-1.
It may be a di-residue represented by a cycloalkyl or aryl group having two, wherein the aryl group may in particular be a phenyl or biphenyl group.

In a most preferred embodiment, A is a space group selected from the examples and their A groups described in Tables 1, 7 and 8 below and the examples and their B groups described in Examples and Table 8 below. .

In a most preferred embodiment, the compound of formula I is 1,3-bis [(2-aminobenzimidazol-1-yl) methyl] cyclohexane, 1,6-bis (2-aminobenzimidazol-1- Yl) hexane, 1,4-bis (2-aminobenzimidazol-1-yl) butane, 1,3-bis (2-aminobenzimidazol-1-yl) propane, 1,2-bis (2-aminobenz Imidazol-1-yl) ethane, α, α′-bis (2-aminobenzimidazol-1-yl) -para-xylene, α, α′-bis (2-aminobenzimidazol-1-yl) -meta- Xylene, 1,3-bis (2-aminobenzimidazol-1-yl) benzene, 3,3′-bis (2-aminobenzimidazol-1-yl) biphenyl Or cis and (or) trans-1,5-bis (2-amino-benzimidazole -1
-Yl) cyclooctane.

Formula II

[0025]

Embedded image Wherein R ¹ is a mono- or polycyclic aryl group, an aralkyl group, a mono- or polycyclic heterocyclic group. The aryl group, aralkyl group and heterocyclic group may be halogen, alkyl, alkoxy, , Alkoxyalkyl, cyano, trifluoromethyl, phenyl, guanidino (this guanidino may be optionally substituted by alkyl, phenyl or benzyl), primary, secondary or tertiary amino groups, ie alkyl groups optionally substituted one or more times by one or two times substituted amino group (-NH _2, -NH- alkyl and -N (alkyl) ₂₎ substituent selected from the group consisting of the ── ──, or the single - or multi bound to cyclic heterocyclic group, a monocyclic or polycyclic ants Lumpur groups described above, R ² is hydrogen, alkyl Or an CF _3. ] The aminobenzimidazole derivative represented by these.

An example of a preferred aryl group is phenyl.

An example of a preferred aralkyl group is benzyl.

Examples of preferred heterocyclic groups are pyrazolyl, imidazolyl, thiazolyl and isothiazolyl.

In a further preferred embodiment, R ¹ is a mono- or polycyclic aryl group or a mono- or polycyclic heterocyclic group selected from the examples and the R ¹ group described in Table 2 below. In a more preferred embodiment, R ¹ is phenyl, benzyl,
Pyrazolyl, imidazolyl, thiazolyl and isothiazolyl.

In a most preferred embodiment, R ² represents a substituent selected from the examples and its R ² group as described in Table 2 below.

In a most preferred embodiment, the compound of formula II is 2-amino-1- [4- (4-chlorophenyl) -2-thiazolyl] benzimidazole, 2-amino-1- (4-dimethylaminobenzyl) -5-trifluoromethylbenzimidazole, 2-amino-1- (4-phenyl-2-thiazolyl) benzimidazole, 2-amino-1- [3- (1,3,5-trimethylpyrazol-4-yl) Phenyl] benzimidazole, 2-amino-1- (4- (N- (2-thiazolyl) amino) phenyl) benzimidazole, 1- (4- (2-aminobenzimidazol-1-yl) phenyl) -3- Phenylguanidine 2-amino-1- (4-acetamidophenyl) benzimidazole or 2-amino-1- (4-amino Phenyl) - benzimidazole.

Formula III

[0033]

Embedded image (Wherein R ¹ and R ² may be the same or different and represent hydrogen, alkyl, mono- or polycyclic heterocyclic group, mono- or polycyclic aryl group, aralkyl group, The group, aryl or aralkyl group is optionally halogen, alkyl, alkoxy, alkoxyalkyl, cyano, trifluoromethyl, phenyl, guanidino, which may be optionally substituted by alkyl, phenyl or benzyl. first, selected from secondary or tertiary amino group, the group consisting of one or two times substituted amino group by ie alkyl group (-NH _2, -N H- alkyl and -N (alkyl) ₂₎ May be substituted one or more times by the substituted substituents.).

Examples of preferred heterocyclic monocyclic groups of the present invention include furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl and thienyl.

Examples of preferred heterocyclic polycyclic groups according to the invention are benzimidazolyl, indolyl, isoquinolyl, quinolyl, acridinyl, phenazinyl and phenathazinyl.

Examples of preferred aryl groups according to the present invention are phenyl, naphthyl and anthracenyl.

An example of a preferred aralkyl group according to the present invention is benzyl.

In a most preferred embodiment, R ¹ represents a substituent selected from the examples and the R ¹ groups described in Table 3 below.

[0039] In a most preferred embodiment, R ² represents a substituent selected from the examples and the R ² groups described in Table 3 below.

In a most preferred embodiment, the compound of formula III is 1- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (3- (trifluoromethyl) phenyl) guanidine, 1- (4 -Chlorobenzyl) -3- (3-trifluoromethylphenyl) guanidine, 1- (5-chloro-2-methoxyphenyl) -3- (3- (trifluoromethyl) phenyl) guanidine, 1,3-bis ( 3- (trifluoromethyl) phenyl) guanidine, 1- (2-bromo-5- (trifluoromethyl) phenyl) -3- (5- (trifluoromethyl) phenyl) guanidine, 1- (4-aminophenyl) Guanidine, α, α′-bis (3-phenylguanidin-1-yl) -para-xylene or 6-amino-3-guanidinoacridi It is.

Formula IV

[0042]

Embedded image中 where R¹And R^TwoMay be the same or different and represent hydrogen, a mono- or polycyclic aryl group or an aralkyl group, and the aryl group and the aralkyl group may optionally be Primary, secondary or tertiary amino groups, i.e. amino groups substituted once or twice with alkyl groups (-NH_Two, -NH-alkyl and -N (alkyl)_Two) May be substituted one or more times with a substituent selected from the group consisting of^ThreeIs a divalent mono- or polycyclic heterocyclic group, a divalent mono- or polycyclic aryl group, a divalent aralkyl group.This heterocyclic group, aryl group and aralkyl group may be halogen, alkyl, Alkoxy, alkoxyalkyl, cyano, trifluoromethyl, primary, secondary or tertiary amino groups, wherein the secondary or tertiary amino groups have been (once or twice) substituted by alkyl or phenyl groups; Often, the phenyl group is optionally substituted one or more times with a substituent selected from the group consisting of halogen, trifluoromethyl, and / or cyano.) May be substituted once or more times by a substituent represented by the formula:-(CH_Two)_C-(Wherein c is a number of 1, 2, 3, 4 or 5), or the other mono- or polycyclic aryl group described above, A divalent bridging group, optionally linked via oxygen, sulfur or nitrogen, wherein a nitrogen atom is added by said mono- or polycyclic aryl group to form a tertiary amino group The monocyclic or polycyclic aryl group to form the above-mentioned monocyclic or polycyclic aryl group.  Show. A guanidine derivative represented by｝.

Examples of preferred R ¹ and R ² groups are phenyl and benzyl, which are optionally substituted one or more times by halogen and / or a primary amino group. Preferably, the substituents are in the ortho and / or para positions.

[0044] Examples of preferred R ³ groups are divalent phenyl groups or divalent phenyl groups bridged by nitrogen to form a secondary or tertiary amino group (this tertiary amino group is preferably an additional And the phenyl group may be optionally substituted by halogen, trifluoromethyl or cyano).

In a most preferred embodiment, R ¹ represents a substituent selected from the examples and the R ¹ groups described in Table 4 below.

[0046] In a most preferred embodiment, R ² represents a substituent selected from the examples and the R ² groups described in Table 4 below.

[0047] In a most preferred embodiment, R ³ represents a substituent selected from the examples and the R ³ groups described in Table 4 below.

In a most preferred embodiment, the compound of formula IV is: 5-chloro-1,3-bis- (4-chlorobenzyl) -2-iminobenzimidazoline, 12- (3-chloro-4-cyanophenyl) -6-imino-5,7,12-triaza-di-benzo [a, f] cyclooctane, 1- (2-aminophenyl) -2-imino-3-phenyl-imidazolidine or 6-imino-5. 7,12-triaza-di-benzo [a, f] cyclooctane.

[0049] Formula VRLR (V) wherein L is from a space group containing 1-20 atoms, a space group containing 2-20 atoms, or 2-20 distant bonds. R represents a mono- or polycyclic aryl group, an aralkyl group or one or more mono-
Or a polycyclic heterocyclic group (the heterocyclic group preferably has one or more nitrogen atoms as a hetero atom) or a mono- or polycyclic aryl group or an aryl group bonded to the heterocyclic group as described above. Show. A symmetric compound represented by｝.

The R group having a tertiary nitrogen atom may be quaternized, in particular with an alkylating agent, preferably an alkyl halide, for example the chloride, bromide or iodide of methyl or ethyl.

A space group, L is, in particular, a linear or branched alkylene chain having 2 to 5 carbon atoms, of the formula — (CH ₂ ) _a —D— (CH ₂ ) _b —, wherein a and b are May be the same or different, and represent a number of 0, 1, 2, 3, 4, or 5;
A di-residue or a mono- or polycyclic heterocyclic group represented by a cycloalkyl or aryl group having 12 (the aryl group may in particular be a phenyl or biphenyl group); Heterocyclic groups preferably have one or more nitrogen atoms as heteroatoms.)

An example of a preferred aryl group is phenyl.

Preferred heterocyclic groups are pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl and piperazinyl.

R is preferably a nitrogen-containing heterocyclic ring bonded to a nitrogen-containing heteroaromatic ring (heteroaryl), wherein the nitrogen-containing heterocyclic ring is preferably piperazinyl, and the nitrogen-containing heteroaryl is pyrimidinyl Is preferable.)
Alternatively, it may be a nitrogen-containing heteroaromatic ring (heteroaryl) (in this case, the nitrogen-containing heterocyclic ring is preferably benzimidazole bonded to an aralkyl group, and the aralkyl group is preferably benzyl).

In a most preferred embodiment, L is the same as the examples and their L described in Table 5 below.
Indicates a space group selected from the groups.

[0056] In a most preferred embodiment, R is the same as the examples and their R as described in Table 5 below.
Indicates a space group selected from the groups.

In a most preferred embodiment, the compound of formula V is α, α′-bis (1- (2-pyrimidyl) piperazin-4-yl) -para-xylene, α, α′-bis (1- ( 2-pyrimidyl) -4-methylpiperazinium-4-yl) -para-xylene or 1,4-bis (1-benzylbenzimidazol-2-yl) piperazine.

Formula VI

[0059]

Embedded image Wherein R ¹ , R ² and R ⁴ may be the same or different and are hydrogen, alkyl, phenyl or benzyl, which phenyl or benzyl optionally comprises halogen, trifluoromethyl and cyano May be substituted one or more times with a substituent selected from the group and R ³ is hydrogen, halogen, trifluoromethyl, cyano, alkyl, phenyl or benzyl.) .

In the most preferred embodiment, R ¹ represents a substituent selected from the examples and the R ¹ groups described in Table 6 below.

In a most preferred embodiment, R ² represents a substituent selected from the examples and the R ² groups described in Table 6 below.

In a most preferred embodiment, R ³ represents a substituent selected from the examples and the R ³ groups described in Table 6 below.

In a most preferred embodiment, R ⁴ represents a substituent selected from the examples and the R ⁴ groups described in Table 6 below.

[0064] In a most preferred embodiment, the compound of formula VI is 1- (4'-chlorobenzyl) -2-dimethylamino) -5-trifluoromethylbenzimidazoline.

[0065] Formula VII

[0066]

Embedded image Wherein A is a space group having the meaning described for group A in formula I above, and X is hydrogen, halogen, trifluoromethyl, cyano, alkoxy, alkoxyalkyl, alkyl, phenyl or benzyl The phenyl or benzyl may be optionally substituted one or more times with a substituent selected from the group consisting of halogen, trifluoromethyl and alkyl, or a mono- or polycyclic heterocyclic group (this heterocyclic group). The radical preferably has one or more nitrogen, oxygen or sulfur atoms as heteroatoms.), Said heterocyclic radical optionally being a group consisting of halogen, trifluoromethyl, alkoxy, alkoxyalkyl or alkyl. Is substituted one or more times by a substituent selected from Bis (benzimidazole) derivatives represented by the household.).

In a most preferred embodiment, A is the example and its A described in Table 7 below.
Shows a substituent selected from the groups.

In a most preferred embodiment, X is X in the Examples and Table 7 below.
Shows a substituent selected from the groups.

[0069] In a most preferred embodiment, the compound of formula VII is cis and / or trans-1,4-bis [(2-chlorobenzimidazole-
1-yl) methyl] cyclohexane, cis and / or trans-1,4-bis [2- (1-pyrrolidinyl) benzimidazol-1-yl) methyl] cyclohexane, cis and / or trans-1,4- Bis [2- (4-morpholinyl) benzimidazol-1-yl) methyl] cyclohexane, cis and / or trans-1,4-bis [2- (1-methylpiperazine-4-
Yl) benzimidazol-1-yl) methyl] cyclohexane or α, α'-bis (1-benzimidazolyl) -meta-xylene.

Formula VIII

[0071]

Embedded image Wherein A and B may be the same or different and represent a space group having the meaning described for group A in Formula I above, and X is as described in Formula VII above. And Y represents a halide, preferably chlorine, bromine or iodine.) A bis (benzimidazolium) derivative represented by the formula:

[0072] In the most preferred embodiment, A and B represent space groups selected from the examples and the A groups described in Tables 1, 7 and 8 below.

In a most preferred embodiment, the compound of formula VIII is 1,1 ′-(α, α ′
-Para-xylylene) -3,3 '-(α, α'-meta-xylylene) -bis (benzimidazolium) bromide.

Definition of Substituents In the context of the present invention, a space group refers to a substituent that links two molecular moieties and imparts a spatial relationship determined relative to these moieties. Space groups can also be referred to as linking or bridging groups. The space group of the present invention must link the two molecular moieties not too close to each other and not too far from each other. It is generally believed that space groups having from 2 to 20 atoms satisfy this need. Examples of such space groups are described herein and are summarized as follows.

[0075]

[Outside 1]

[0076]

[Outside 2] In the present invention, the halogen is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present invention, alkyl represents a monovalent saturated linear or branched hydrocarbon chain. The hydrocarbon chain preferably has 1 to 18 carbon atoms (C _1-18 alkyl), more preferably has 1 to 6 carbon atoms (C _1-6 alkyl; lower alkyl), pentyl, isopentyl , Neopentyl, t-pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl represents C _1-4 alkyl and includes butyl, isobutyl, sec-butyl and tert-butyl. In a preferred embodiment of the invention, alkyl represents C _1-3 alkyl, which may in particular be methyl, ethyl, propyl or isopropyl.

In the present invention, the cycloalkyl group preferably represents a cyclic alkyl group having 3 to 7 carbon atoms (C _3-7 cycloalkyl), and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. I do.

[0079] In the present invention, an alkoxy group refers to an "alkyl-O-" group, wherein alkyl is as defined above.

[0080] In the present invention, an alkoxy-alkyl group refers to an "alkyl-O-alkyl-" group, where alkyl is as defined above.

[0081] In the present invention, the first (-NH ₂₎ amino group, a second (-NH- alkyl), or tertiary (-N-(alkyl) ₂₎ may be an amino group, i.e. an amino group the above alkyl It may be substituted once or twice.

In the present invention, the mono- or polycyclic aryl group represents a mono- or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups according to the invention are phenyl, naphthyl and anthracenyl.

In the present invention, the aralkyl group is the above-mentioned mono- or polycyclic aryl group,
The aryl group is also attached to the alkyl described above. An example of a preferred aralkyl group according to the invention is benzyl.

In the present invention, a mono- or polyheterocyclic group is a mono- or polycyclic compound having one or more heteroatoms in a ring structure. One or more ring structures may be especially aromatic (ie, heteroaryl). Preferred heterocyclic monocyclic groups of the present invention are 5- or 6-membered heterocyclic monocyclic groups. Examples of preferred heterocyclic monocyclic groups of the present invention include furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5
-Oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl and thienyl. Examples of preferred heterocyclic polycyclic groups according to the present invention are benzimidazolyl, indolyl, isoquinolyl and quinolyl.

Further, in the present invention, the compound having a tertiary amino group may also be quaternized with an alkylating agent, especially an alkyl halide, preferably chloride, bromide or iodide of methyl or ethyl. .

Specific Examples In the most preferred embodiment, the compounds of the present invention are selected from the examples and the compounds described in Tables 1-8 below. Table 1 Compounds of Formula I

[0087]

[Table 1] Table 2 Compounds of Formula II

[0088]

[Table 2] Table 3 Compounds of Formula III

[0089]

[Table 3] Table 4 Compounds of Formula IV

[0090]

[Table 4] Table 5 Compounds of Formula V

[0091]

[Table 5] Table 6 Compounds of Formula VI

[0092]

[Table 6] Table 7 Compounds of Formula VII

[0093]

[Table 7] Table 8 Compounds of Formula VIII

[0094]

[Table 8] Stereoisomers The compounds of the invention can exist in (+) and (-) forms as well as in racemic form. The racemates of these isomers and the individual isomers themselves are included in the scope of the present invention.

Racemic forms can be resolved into optical antipodes by known methods and techniques. One way to separate the diastereomeric salts is by the use of an optically active acid and by treating the liberation of the optically active amine compound with a base. Another method for resolving racemates into the optical antipodes is based on chromatography on an optically active matrix. Thus, the racemates of the present invention can be resolved into their optical enantiomers, for example, by fractional crystallization of d- or l-salts (tartrate, mandelate, or camphorsulfonate).

The compounds of the present invention may also be used in combination with a compound of the present invention and an optically activated carboxylic acid such as (+) or (−) phenylalanine, (+) or (−) phenylglycine, (+ ) Or (−) by reacting a carboxylic acid derived from camphoric acid to form diastereomeric amides, or by reacting a compound of the present invention with an optically active chloroformate to form diastereomeric carbamates. Can be divided by

[0097] Other methods for resolving optical isomers are known in the art. Such a method is described in Jaques J, Collet A, & Wilen S, "Enantiomers, Racemates, and Resolu
tions " , John Wiley and Sons, New York (1981).

In addition, some compounds of the invention that are oximes may have two forms, a syn-form and an anti-form (Z- and anti-), depending on the configuration of substituents around the -C = N- double bond. E-form). Thus, the compounds of the present invention may be in their syn- and anti-forms (Z- and E-forms) or in mixtures thereof.

Pharmaceutically Acceptable Salts The compounds of the present invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts and pre- and prodrug forms of the compounds of the present invention.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as hydrochloride derived from hydrochloric acid, odor derived from hydrobromic acid. Hydrochloride, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, acetic acid derived from acetic acid Salt, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citric acid Citrate derived from acid, embonic acid derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamate Glutamate derived from acid, glycolate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, Methanesulfonic acid salt derived from methanesulfonic acid, naphthalene-2-sulfonic acid salt derived from naphthalene-2-sulfonic acid, phthalic acid salt derived from phthalic acid, salicylic acid salt derived from salicylic acid, sorbin derived from sorbic acid Acid salts, stearic acid salts derived from stearic acid, succinic acid salts derived from succinic acid, tartaric acid salts derived from tartaric acid, and toluene-p-sulfonic acid salts derived from toluene-p-sulfonic acid. Such a salt can be produced by a conventionally known method.

Other acids, such as oxalic acid, which is not itself considered to be pharmaceutically acceptable, may be used in preparing the compounds of the invention and their pharmaceutically acceptable acid addition salts. Suitable for the production of salts useful as intermediates.

The metal salts of the compounds of the present invention include the alkali metal salts, for example, the sodium salts of the compounds of the present invention containing a carboxy group. The compounds of the present invention may be provided in soluble or insoluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Dissolvable forms can also include hydrated forms, such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like. In general, a soluble form is considered to correspond to a non-dissolvable form for the purposes of the present invention.

Preparation Methods The compounds of the present invention can be prepared by conventional chemical synthesis methods, for example, the methods described in the Examples. Starting compounds for the treatment according to the invention are known or can easily be prepared from commercially available compounds in a customary manner.

The end products of the reactions described herein can be isolated by conventional processing, for example, extraction, crystallization, distillation, chromatography and the like. Biological Activity Compounds of the present invention have been found in particular in vitro experiments to be useful as potassium channel blockers. More specifically, the compounds of the present invention are capable of selectively blocking SK channels, such as SK1, SK2 and / or SK3 channels.

As described in the examples, all compounds tested are in the sub-micromolar range and in the lower micromolar range, ie from about 1 μM to about 10 μM (below 1 to abo
(ve 10 μM) in the range of biological activity measured as IC ₅₀ . Preferred compounds of the present invention have submicromolar and low micromolar ranges, ie, about 1
The biological activity measured as described herein in the range of μM to about 100 μM (below 1 to about 100 μM).

Thus, according to another aspect, the present invention uses a compound of the present invention for the manufacture of a medicament that is useful for treating or reducing a disease or disorder associated with potassium channel activity, especially SK channel activity. About the method.

In a further preferred embodiment, the compounds according to the invention are used for conditions such as diseases or respiratory diseases, for example asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary convulsions, Renal impairment, renal polycystic disease, bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemic heart disease, angina, coronary heart disease, traumatic brain injury , Mental illness, anxiety, depression, dementia, memory and attention deficit, Alzheimer's disease, dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmia, hypertension, apsans seizures, myotonic muscular dystrophy, Used in the manufacture of a medicament for the treatment or alleviation of xerostomia, diabetes type II, hyperinsulinemia, preterm birth, baldness, cancer and immunosuppression be able to.

Drugs [0108] In yet another aspect, the present invention provides novel drugs containing a therapeutically effective amount of a compound of the present invention.

[0109] When administering a compound of the invention for use in therapy in the form of a crude compound, the active substance may be administered as one or more left-hand drugs, excipients, optionally in the form of a physiologically acceptable salt in the drug. It is preferably added in the form of a pharmaceutical preparation together with the agent, carrier and / or diluent.

In a preferred embodiment, the present invention relates to a compound of the invention or a pharmaceutically acceptable salt or derivative thereof, comprising one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic ingredients. (Or) A pharmaceutical composition is provided that contains a prophylactic component. The carrier must be acceptable in the sense that it is compatible with the other ingredients in the formulation and is not harmful to the patient to whom it is administered.

The medicament of the present invention is suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (intramuscular, subcutaneous and intravenous) administration or inhalation or insufflation It is a form suitable for.

The compounds of the invention together with the usual adjuvants, carriers or diluents may be formulated into the drug and its unit dosage forms in solid form, such as tablets or filled capsules, or liquid forms such as solutions, suspensions, emulsions, elixirs or the like. Capsules filled by this,
It is used in all forms for oral use, in the form of suppositories for rectal administration, or in the form of a sterile injectable solution for parenteral (including subcutaneous) use. Such drugs and their unit dosage forms
Containing the usual ingredients in the usual proportions, with or without additional active compounds or components,
Such unit dosage form contains a suitable, effective amount of the active ingredient, corresponding to the planned daily dosage range employed.

The compounds of the present invention can be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the dosage forms described below may contain either the compound of the present invention or a pharmaceutically acceptable salt thereof as the active ingredient.

[0114] Pharmaceutically acceptable carriers for the manufacture of a medicament from the compounds of the present invention are either solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier is one or more substances that may act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrants or encapsulating materials. be able to.

[0115] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

The powders and tablets contain about 5 or 10 to about 70% of the active substance. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, teguistrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like.
The term "manufacturing" includes the preparation of an active substance using the encapsulating material as a carrier to provide a capsule encapsulated by the carrier with or without the carrier. Similarly, cashiers and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solids suitable for oral administration.

For preparing suppositories, a low-boiling wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring.
The molten homogeneous mixture is then poured into regular sized molds, allowed to cool, and thereby to solidify.

Formulations suitable for vaginal administration are prepared as pessaries, tampons, creams, gels, pastes, foams or sprays which contain, in addition to the active ingredient, suitable carriers conventionally known.

Solutions include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection solutions can be prepared as solutions in aqueous polyethylene glycol solution.

The compounds of the present invention are prepared for parenteral administration (eg, by injection, eg, by bolus injection or continuous infusion), and are presented in unit dosage form in ampules, pre-filled syringes, small doses of infusion or Present with preservatives added in various dosing containers. Formulating the formulation as a suspension, solution or emulsion in an oily or aqueous vehicle,
It contains preparations such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid, or by lyophilization of a suitable excipient, such as sterile pyrogen-free water, from solution before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.

An aqueous suspension suitable for oral use is prepared by mixing the finely divided active ingredient in water with a viscous substance, for example a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspensions. It can be manufactured by suspending.

Shortly before use, there may also be mentioned solid preparations which can be converted into liquid form for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis, the chemicals of the invention are prepared as ointments, creams or lotions, or as a transdermal patch. Ointments and creams are prepared using an aqueous or oily base with the addition of suitable thickening and / or gelling agents, for example. Lotions are prepared using an aqueous or oily base, which generally contains one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Drugs suitable for topical administration in the mouth include flavor bases, lozenges containing the active ingredient in sucrose and acacia or tragacanth, inert bases such as gelatin and glycerin or sucrose or the active ingredient in acacia. Containing pastel,
And mouthwashes containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are administered directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The drug may be supplied in a single or multi-dose form. In the case of a dropper or pipette, this may be accomplished by administering to the patient an appropriate predetermined amount of the solution or suspension. In the case of a spray, this is achieved for example by means of a metering spray pump.

Administration to the respiratory tract is accomplished by an aerosol formulation. The active ingredient is supplied in this aerosol by pressurized-packing with a suitable propellant, for example, chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosols also usually contain a surfactant such as lecithin. The dosage of the drug is adjusted by the supply of a metering valve.

Alternatively, the active ingredient is supplied in the form of a dry powder, for example in the form of a powder mixture of the chemical in a suitable powder base, for example lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Usually, the powder carrier will form a gel in the nasal cavity. Powder formulations are presented in unit dosage form, for example, in gelatin capsules or cartridges, or in effervescent packs from which the powder is administered by means of an inhaler.

In formulations for administration to the respiratory tract (including intranasal formulations), the chemical will generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by a conventionally known method, for example, pulverization into fine particles.

When desired, suitable formulations are used to maintain the release of the active ingredient.

The medicament is preferably in unit dosage form. In such form, the drug is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred formulations.

Further details regarding formulations and methods of administration can be found in Remington's Pha
rmaceuticalSciences (Macack PublishingC
o. , Easton, PA).

A therapeutically effective dose refers to that amount of the active ingredient that ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, such as ED ₅₀ and LD ₅₀ , can be measured in cell cultures or experimental animals by standard pharmacological procedures. The dose ratio between therapeutic and toxic effects is a therapeutic index and can be expressed by the ratio LD ₅₀ / ED ₅₀ . Pharmaceutical formulations that exhibit large therapeutic indices are preferred.

Of course, the dosage administered must be carefully adjusted to the age, weight, and condition of the patient to be treated, as well as, the route of administration, dosage form and eating habits, and the desired result,
The exact dosage must of course be determined by a physician.

The active ingredients can be administered in one or several daily doses. Formulations containing from about 0.1 to about 500 mg, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg of the active ingredient per unit dose are currently considered suitable for therapeutic treatment. Methods of Treatment In another aspect, the present invention provides a method of treating a disorder or disease in living organisms, including humans.
In a method of treating or alleviating {the disorder or disease responds to blockade of potassium channels, particularly SK channels}, a therapeutically effective amount of a compound of the present invention may be used to treat a human in need thereof. Characterized in that it is administered to animal organisms, including
It relates to the above method.

In a preferred embodiment of the method of the present invention, the disease or disorder is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary convulsions, renal impairment, polycystic kidney disease , Bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, intracerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain Disorders, mental illness, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Lenneau's disease, intermittent claudication, Sjogren's syndrome, migraine, arrhythmias, hypertension, apsans seizures, myotonic muscular dystrophy , Xerostomia, diabetes type II, hyperinsulinemia, preterm birth, baldness, cancer and immunosuppression.

Satisfactory results have, in some cases, been 0.005 mg / kg iv and 0.01 mg / kg
It can be obtained at dosages as low as kg intraperitoneally. The upper limit of the dosage range is about 10
mg / kg and 100 mg / kg. The preferred range is about 0.001 mg / k
g to about 1 mg / kg i.v. and about 0.1 mg / kg to about 10 mg / kg i.p.

Examples The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

Example 1 Basic Reaction Scheme for the Synthesis of Compounds 1a-1f (see Table 1)

[0142]

Embedded image 1,4-bis (2-aminobenzimidazol-1-yl) butane, 2HCl
(Compound 1c) 1.2c.2HCl (1.1 g, 3.2 mmol) in anhydrous DMF (10 ml)
) Is wrapped in aluminum foil (alu-foil) to block light. A solution of cyanogen bromide (0.7 g, 6.6 mmol) in anhydrous DMF (5 ml) is added dropwise. The mixture is stirred for 3 days at ambient temperature in a nitrogen atmosphere. Thereafter, the solution is poured into ice water. The precipitate was filtered, washed with water, dried and dried at 1c (0.42
g) remains. Melting point 292-294 [deg.] C. 1,6-bis (2-aminobenzimidazol-1-yl) hexane, 2HCl
(Compound 1b) is similarly prepared from 1.2b. 145-147 ° C. 1,3-bis (2-aminobenzimidazol-1-yl) propane (compound 1
d) is prepared analogously from 1.2b. The product is isolated as the free base. Melting point 2
20 ° C (decomposition).

Example 2 1,3-Bis [(2-aminobenzimidazol-1-yl) methyl] cyclo
The xane (compound 1a) is prepared from 1.2a as described in Example 1 with the following changes: the solvent is anhydrous NMP. The reaction time is 24 hours. At the end of the reaction, the mixture is poured into water and made alkaline by addition of aqueous sodium carbonate solution.
The precipitate is filtered and purified by column chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (9: 1: 0.1 v / v / v) as eluent. Yield: 0.28 g (cis / trans mixture).
This mixture gradually decomposes while melting. α, α′-Bis (1-aminobenzimidazol-1-yl) -para- xylene (Compound 1f) is similarly prepared from 1.2f. Melting point 287-289 [deg.] C. α, α′-bis (1-aminobenzimidazol-1-yl) -meta-xylene (compound 1 g) is similarly prepared from 1.2 g. Melting point 279-280 [deg.] C. 3,3′-Bis (1-aminobenzimidazol-1-yl) biphenyl (Compound 1i) is similarly prepared from 1.2i. 160-163 ° C. 1,3-bis (2-aminobenzimidazol-1-yl) benzene (compound 1
h) is prepared similarly from 1.2 h using DMF as solvent. Melting point 270-2
75 ° C. 1,2-bis (2-aminobenzimidazol-1-yl) ethane (compound 1e
) Is prepared from 1.2e analogously to Example 2 using DMF as solvent and a total of 4 equivalents of cyanogen bromide. The reaction time is 6 days. Yield: 0.13 g. Melting point 257-
258 ° C.

Example 3 N, N'-bis (2-aminophenyl) -1.4-butanediamine, 2HCl
(Compound 1.2c): To a suspension of 1.3c (1.2g, 3.64mmol) in a mixture of anhydrous EtOH and dichloromethane (50ml, 9: 1) was added Pd-catalyst (0.1g,
5% Pd supported on activated carbon) is added. The mixture H ₂ - hydrogenated at ambient pressure until absorption stopped, then filtered through celite. The filtrate is concentrated to a small volume under reduced pressure. Ethereal hydrogen chloride is added and the product is isolated by filtration. Yield: 1.14 g. 1,3-bis (N- (2-aminophenyl) methylamine) cyclohexane, 2
HCl (compound 1.2a) is similarly prepared from 1.3a. N, N'-bis (2-aminophenyl) -1,6-hexanediamine, 2HCl
(Compound 1.2b) is similarly prepared from 1.3b. N, N'-bis (2-aminophenyl) -1,3-propanediamine, 2HCl
(Compound 1.2d) is similarly prepared from 1.3d. N, N'-bis (2-aminophenyl) ethylenediamine, 2HCl (Compound 1
. 2e) is similarly prepared from 1.3e. N, N'-bis (2-aminophenyl) -meta-xylylenediamine, 2HCl
(Compound 1.2 g) is similarly prepared from 1.3 g. N, N'-bis (2-aminophenyl) -1,3-phenylenediamine, 2HC
l (Compound 1.2h) is prepared analogously from 1.3h. N, N'-bis (2-aminophenyl) -3,3'-diaminobiphenyl, 2H
Cl 2 (compound 1.2i) is similarly prepared from 1.3i.

Example 4 N, N′-bis (2-aminophenyl) -para-xylylenediamine (Compound 1
. 2f): 1.3f (8.7 g, 2: 1) in absolute EtOH and THF (500 ml, 1: 1).
3.0 mmol) in a suspension containing sodium sulfide nonahydrate (55.
5 g, 0.23 mol) and ammonium chloride (12.3 g, 0.23 mol) are added. The resulting mixture is heated at reflux for 3 days. The solvent is removed by evaporation and the residue is triturated with water. The crude product is filtered, diethyl ether and methanol (
Extract with a refluxing mixture of 200 ml, 1: 1). The cooled extract is concentrated and purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1 v / v) as eluent. Yield: 1.87 g.

Example 5 N, N′-bis (2-nitrophenyl) -1,4-butanediamine (Compound 1.
3c): 1,4-butanediamine (0.51 ml, 5 ml) in anhydrous DMF (5 ml)
. 0 mmol), 1-fluoro-2-nitrobenzene (1.1 ml, 10.0 m
mol) and triethylamine (1.39 ml, 100 mmol) is heated to 100 ° C. overnight. Pour the cooled mixture into ice water. The product is filtered, washed with water and dried to give 1.22 g (24%). 1,3-Bis [N- (2-nitrophenyl) aminomethyl] cyclohexane (Compound 1.3a) is similarly prepared from 1,3-bis (aminomethyl) cyclohexane. N, N'-bis (2-nitrophenyl) -1,6-hexanediamine (compound 1
. 3b) is prepared analogously from 1,6-hexanediamine. N, N'-bis (2-nitrophenyl) -1,3-propanediamine (compound 1
. 3d) is prepared analogously from 1,3-propanediamine. N, N'-bis (2-nitrophenyl) ethylenediamine (Compound 1.3e) is similarly prepared from ethylenediamine. N, N'-bis (2-nitrophenyl) -para-xylylenediamine (compound 1
. 3f) is prepared analogously from para-xylylenediamine. N, N'-bis (2-nitrophenyl) -meta-xylylenediamine (compound 1
. 3g) is prepared analogously from meta-xylylenediamine. N, N'-bis (2-nitrophenyl) -1,3-phenylenediamine (Compound 1.3h) is similarly prepared from 1,3-phenylenediamine. N, N'-bis (2-nitrophenyl) -3,3'-dianobiphenyl (compound 1.3h) is similarly prepared from 3,3'-diaminobiphenyl.

Example 6

[0148]

Embedded image 1- (4-aminophenyl) guanidine, HI (compound 3f): anhydrous EtOH (
1,4-phenylenediamine (20 ml) and a mixture of THF (10 ml).
1.08 g, 10.0 mmol) in a solution containing methylthiuronium iodide (
1.69 g, 7.75 mmol) are added. Heat the mixture to 60 ° C. for 3 days. After cooling, the solvent is removed by evaporation and the residue is extracted with water. The extract is evaporated to dryness and the residue is washed with ether, leaving 3f. Melting point 195-197 [deg.] C.

Example 7

[0150]

Embedded image α, α'-bis (3-phenylguanidin-1-yl) -para-xylene, 2H
Cl (Compound 3g): Aniline (1.37 ml, 15.3 ml) in DMF (25 ml).
(0 mmol), concentrated hydrochloric acid (0.23 ml) is added. Mixture D
N, N'-dicyano-para-xylylenediamine (0.7 ml) in MF (10 ml).
g, 3.76 mmol) with stirring for 30 minutes prior to the addition of the suspension. Heat the resulting mixture to 100 ° C. for 4 days. Removing the solvent by evaporation under reduced pressure;
The residue is extracted with EtOH. The concentrated extract is purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Ethereal hydrogen chloride is added to the eluent containing the product. The product is filtered and dried. Yield: 0.18 g. 204-207 ° C.
N, N'-dicyano-para-xylylenediamine : To a suspension of para-xylylenediamine (1.88 g, 3.8 mmol) in THF (50 ml) was added TH.
A solution of cyanogen bromide (1.06 g, 10.0 mmol) in F (50 ml) is added. The reaction vessel is wrapped in aluminum foil and the mixture is left stirring for 3 days at ambient temperature. The mixture was filtered and the filtrate was evaporated to dryness to give the desired product (0.7
1 g) remain.

Example 8

[0152]

Embedded image 6-amino-3-guanidinoacridine, HCl (compound 3h): 3,6-diaminoacridine (0.5 g, 1.0 mm) in concentrated hydrochloric acid (10 ml)
ol), add cyanamide (0.18 g, 4.3 mmol). Heat the mixture to 100 ° C. for 6 days. The cooled mixture is poured into ice water and made alkaline by the addition of aqueous sodium hydroxide solution. The precipitate is filtered and purified by column chromatography on silica gel using a mixture of acetonitrile, ethyl acetate and water (4: 1: 1 v / v / v) as eluent. The fractions containing the product are concentrated and the product is precipitated while adding ethereal hydrogen chloride. Yield: 30 mg. Melting point 305 ° C or higher.

Example 9

[0154]

Embedded image α, α′-bis (1-benzimidazolyl) -meta- xylene (compound 7e): A solution of 1.2 g (1.39 g, 4.37 mmol) in formic acid (5 ml) is heated to 80 ° C. for 30 minutes. . Excess formic acid is removed by evaporation and the residue is stirred with ice-cooled aqueous sodium carbonate solution. The product is filtered, washed with water and dried. Yield: 1.20 g.

Example 10

[0156]

Embedded image 1,1 ′-(α, α′-para-xylylene) -3,3 ′-(α, α′-meta-
Silylene) -bis (benzimidazolium) bromide (compound 7f): DMF (7
0e) and 7e (0.46 g, 1.38 mmol) and α, α'-dibromo-
A solution containing para-xylene (0.36 g, 1.38 mmol) is kept at 100 ° C. overnight.
Heat to The solvent is removed under reduced pressure and the crystalline residue is washed with dichloromethane, leaving 7f (0.76 g). Melting point 292-294 [deg.] C.

Example 11

[0158]

Embedded image Cis / trans-1,4-bis [(2-chlorobenzimidazol-1-yl)
Methyl] cyclohexane (Compound 7a): 1,4-bis (p-toluenesulfonyloxymethyl) cyclohexane (1.10 g, 2.43 mmol), 2-chlorobenzimidazole (0.74 g, 4) in anhydrous EtOH (20 ml) .85 mmol) and potassium carbonate (0.67 g)
, 4.85 mmol) is heated to 75 ° C. for 2 days. Pour the cooled mixture into water, filter the precipitate, wash with water and dry to give 7a (0.61 g). Melting point 247-253 [deg.] C.

Example 12

[0160]

Embedded image Cis / trans-1,4-bis [2- (1-pyrrolidinyl) benzimidazole
-1-yl) methyl] cyclohexane (compound 7b): 7a (0.25 g, 0.61 mmol) and pyrrolidine (2 ml, 24 mmol)
Heat the mixture of 1) to 80 ° C. for 2 hours. After cooling, the mixture is poured into water and the precipitate is filtered. The crude product is recrystallized from a mixture of 2-propanol and dichloromethane (9: 1 v / v) to give 7b (0.12 g). 258-260 ° C
. Cis / trans-1,4-bis [2- (4-morpholinyl) benzimidazole
-1-yl) methyl] cyclohexane, 2HCl (compound 7c) is similarly prepared from 7a and morpholine. Isolated as the hydrochloride salt. Melting point 286-288 [deg.] C. Cis / trans-1,4-bis [2- (1-methylpiperazin-4-yl) ben
[Zimidazol-1-yl) methyl] cyclohexane (compound 7d) is similarly prepared from 7a and 1-methylpiperazine.

Example 13

[0162]

Embedded image α, α'-bis (1- (2-pyrimidyl) piperazin-4-yl) -para-oxy
Ren (Compound 5a): 1- (2-Pyrimidyl) piperazine, 2HCl (2.
0 g, 8.43 mmol), α, α′-dibromo-para-xylene (1.11 g)
, 4.21 mmol) and triethylamine (2.43 ml).
Heat to 00 ° C. The cooled mixture is filtered, the precipitate is dissolved in water and made alkaline by addition of aqueous sodium hydroxide. The product is filtered, washed with water and dried. Yield: 1.91 g. 193-195 ° C.

Example 14

[0164]

Embedded image α, α'-bis (1- (2-pyrimidyl) -4-methylpiperazinium-4-i
) -Para-xylene iodide (compound 5b): 5a (0.7 ml) in a mixture of DMF (1 ml) and dichloromethane (10 ml).
5g, 1. . 74 mmol) in iodomethane (0.22 ml,
3.53 mmol) are added and the mixture is stirred at ambient temperature for 3 days. The product is filtered, washed with dichloromethane and dried. Yield: 0.63 g. Melting point 310 ° C or higher.

Example 15

[0166]

Embedded image 1,4-bis (1-benzylbenzimidazol-2-yl) piperazine (compound 5c): 1-benzyl-2-chlorobenzimidazole (1.
A mixture of 21 g, 5.0 mmol), piperazine (0.22 g, 2.5 mmol) and potassium carbonate (0.69 g, 5.0 mmol) is heated at reflux for 3 days. Pour the cooled mixture into ice water. The precipitate is filtered and washed with refluxing ethyl acetate,
5c remains. Yield: 0.46 g. Melting point 247-248 [deg.] C.

Example 16

[0168]

Embedded image 1- (4'-chlorobenzyl) -2-dimethylamino) -5-trifluoromethyl
Rubenzimidazoline (Compound 6d): To a solution of 2- (4′-chlorobenzylamino) -5-trifluoromethylaniline, HCl (1 g, 2.97 mmol) in DMF (10 ml) was added triethylamine (0.36 g). , 3.56 mmol) and N, N-dimethylformamide dimethyl acetate (0.84 g, 7.12 mmol). The mixture is stirred at 50 ° C. overnight. Partition the cooled mixture between water and diethyl ether. The organic phase is dried and concentrated and the residue is treated with diethyl ether and petroleum ether (1:
1v / v) with the mixture to leave 5c. 107-109 ° C.

Example 17 All reactions in this example involving air-sensitive reagents or intermediates are performed under nitrogen and in anhydrous solvents. Using magnesium sulfate as a desiccant in post-treatment,
The solvent is evaporated under reduced pressure. 2-amino-1- [3- (1,3,5-trimethylpyrazol-4-yl) fe
Nyl] benzimidazole (compound 2d) 2- (3- (2-amino-1-benzimidazole) phenyl) -1,3,2
-Dioxaborinane (2.0 g, 6.82 mmol), 4-bromo-1,3,5
-Trimethylpyrazole (1.29 g, 6.82 mmol), tetrakis (triphenylphosphine) -palladium (O) (0.24 g, 0.20 mmol),
Sodium bicarbonate (2.29 g, 27.3 mmol), water (27 ml) and 1
, 2-Dimethoxyethane (54 ml) is stirred at reflux overnight. An aqueous solution of sodium hydroxide (50 ml) is added and the mixture is extracted twice with ethyl acetate (50 ml). The crude extract is purified by chromatography on silica gel and a mixture of ethanol (4%) and dichloromethane as eluent. The product is isolated as the free base. Yield 0.60 g, 28%. Melting point 198-200 <0> C.

Method A 2-Amino-1- (4-dimethylaminobenzyl) -5-trifluoromethylbe
Nsimidazole (Compound 2b).

2-Amino-N- (4-dimethylaminobenzyl)-in DMF (75 ml)
A mixture containing 5-trifluoromethylaniline (5.2 g, 16.8 mmol) and cyanogen bromide (2.31 g, 21.8 mmol) is stirred for 3 days at room temperature.
Water (100 ml) is added and the mixture is filtered. The filtrate was washed with sodium hydroxide (2M
, 100 ml). The mixture is extracted twice with ethyl acetate (100 ml). The crude extract is purified by chromatography on silica gel and a mixture of ethanol (4%) and dichloromethane as eluent. The product is isolated as the free base. Yield 0.92 g, 16%. Melting point 184-286 [deg.] C. 2-amino-1- [4- (4-chlorophenyl) -2-thiazolyl] benzimi
Dazole hydrochloride (Compound 2a) was prepared according to Method A using 2-amino-N- [4- (
4-chlorophenyl) -2-thiazolyl] -aniline. Melting point 220
-223 ° C. 2-Amino-1- (4-phenyl-2-thiazolyl) benzimidazole (Compound 2c) is prepared from 2-amino-N- (4-phenyl-2-thiazolyl) -aniline according to Method A. Melting point 229-231 [deg.] C. 2-amino-1- (4- (N- (2-thiazolyl) amino) phenyl) benzi
Midazole (Compound 2e) was prepared according to Method A using 2-amino-4- (N- (2-
Prepared from thiazolyl) amino) phenyl) aniline. 218-220 ° C
. 2-Amino-1- (4-acetamidophenyl) benzimidazole is prepared from 2-amino-N- (4-acetamidophenyl) aniline according to Method A. 246-248 ° C. 2- (3- (2-amino-1-benzimidazolyl) phenyl) -1,3,2-
Dioxaborinane was converted to 2-amino-3 ′-(1,3,2-dioxaborinan-2-
Yl) prepared from diphenylamine. 150-155 ° C. 2-amino-1- (4-aminophenyl) benzimidazole hydrochloride.

The 2-amino-N- (4-acetamidophenyl) benzimidazole is refluxed in hydrochloric acid (25 ml) overnight. The crude mixture is evaporated and triturated with diethyl ether. Yield 1.68 g, 96%, mp 258-260 ° C. 1- (4- (2-aminobenzimidazol-1-yl) phenyl) -3-fe
Nilguanidine hydrochloride (Compound 2f).

2-amino-1- (4-aminophenyl) benzimidazole hydrochloride (1.5
8g, 6.06 mmol), phenyl cyanamide (2.79 g, 23.6 mm)
ol) and acetonitrile (10 ml) are refluxed for 3 days. Filter the solid product. The product is recrystallized from acetonitrile (300 ml). Yield 1.
3 g, 57%, mp 265-267 ° C.

Method B 2-Amino-N- (4-dimethylaminobenzyl) -4-trifluoromethyla
Niline N- (4-dimethylaminobenzyl) -2-nitro-4-trifluoromethylaniline (6.0 g, 17.7 mmol), palladium on carbon (0
. 70 g, 5%), ethanol (200 ml) and tetrahydrofuran (175
ml) is stirred under hydrogen until 1.19 L is consumed. The reaction mixture is filtered through a pad of celite and evaporated. Yield 5.35 g, 98%. Melting point 1
60-162 ° C. 2-amino-N- [4- (4-chlorophenyl-2-thiazolyl] aniline is converted to N
Prepared from-[4- (4-chlorophenyl-2-thiazolyl] -2-aniline 2-amino-N- (4-phenyl-2-thiazolyl) aniline hydrochloride is 2-nitro-N- (4-phenyl Prepared from -2-thiazolyl) -2-aniline according to Method B, mp 189-190 ° C. 2-Amino-N- (4-acetamidophenyl) aniline is converted to N- (4-acetamidophenyl) -2-nitroaniline From 2-amino-3 '-(1,3,2-dioxaborinan-2-yl) diphenyla.
The min is prepared according to Method C from 3 '-(1,3,2-dioxaborinan-2-yl) -2-nitrodiphenylamine. 220-222 ° C.

Method C 2-Amino-N- (4- (2-thiazolyl) phenyl) aniline 2-Nitro- N- (4- (2-thiazolylamino ) phenyl) aniline (1.
2 g, 3.8 mmol), sodium sulfide nonahydrate (4.61 g, 19
. 2 mmol), a mixture of ammonium chloride (1.03 g, 19.2 mmol) and ethanol (40 ml) is stirred under reflux for 40 hours. Water (50 ml) is added, the mixture is stirred and filtered. Yield 0.49 g, 46%. Melting point 184-186
° C. N- (4-dimethylaminobenzyl) -2-nitro-4-trifluoromethyla
Niline 4-chloro-3-nitrobenzotrifluoride (5.05 g, 22.4 mm
ol), 4- (dimethylamino) -benzylamine dihydrochloride (5.0 g, 22
. 4 mmol), a mixture of potassium carbonate (9.29 g, 76.2 mmol) and dimethylformamide (60 ml) is stirred at room temperature for 3 days. Water (60 ml) is added and the mixture is stirred for 0.5 hours, then filtered. The crystalline product is triturated with petroleum ether. Yield 6.08 g, 80%. 158-160 ° C.

Method D 2-Nitro-N- (4-phenylthiazol-2-yl) aniline 2-amino-4-phenylthiazole (12.5 g, 80.9 mmol), 1
A mixture of -fluoro-2-nitrobenzene (12.5 g, 89.0 mmol) and potassium carbonate (13.4 g, 97.1 mmol) is stirred at 150 ° C for 24 hours. Water (100 ml) was added and the mixture was twice washed with 1,2-dichloroethane (50 m
Extract in 1). The crude extract is purified by chromatography using silica gel and toluene as eluent. The product is isolated as the free base. Yield 7.
95 g, 33%. 114-116 ° C. N- [4- (4-Chlorophenyl) -2-thiazolyl] -2-nitroaniline is prepared according to Method D. 2-Nitro-N- (4-aminophenyl) aniline is prepared according to Method D. 110-112 ° C. 2-Nitro-N- (4-acetylamidophenyl) aniline is prepared according to Method D. Melting point 164-166 [deg.] C. 3- (2-Nitrophenylamino) phenylboronic acid is prepared according to Method D using dimethylformamide as solvent and 90 ° C. as reaction temperature. Melting point 195-196 [deg.] C. 2-nitro-N- (4- (2-thiazolylamino) phenyl) aniline 2-nitro-N- (4-aminophenyl) aniline (5.0 g, 21.8 mm)
ol), 2-bromothiazole (3.58 g, 21.8 mmol) and potassium carbonate (3.01 g, 21.8 mmol) are stirred at 150 ° C. for 24 hours. Water (2
50 ml) and the mixture is extracted with ethyl acetate (150 ml). The crude extract is purified by chromatography on silica gel and a mixture of ethanol (4%) and dichloromethane as eluent. The product is isolated as the free base. Yield 1.47 g, 22%. Melting point 195-197 [deg.] C. 3 ′-(1,3,2-dioxaborinan-2-yl) -2-nitrodiphenyla
Min 2-nitrodiphenylamine-3'-boronic acid (27.0 g, 105 mmol
l) A mixture of 1,3-propanediol (9.55 g, 126 mmol) and toluene (500 ml) is refluxed for 2 hours using an installed Dean-Stark water separator. Evaporation of the solvent gives the product as a yellow oil. Yield 31 g,
99%.

Method E 1- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (3- (g
( Fluoromethyl) phenyl) guanidine (Compound 3a) 3-Cyanamidobenzotrifluoride (0.40 g, 2.15 mmol)
, 2-methoxy-5-trifluoromethylaniline hydrochloride (0.53 g, 2.3
A mixture of 3 mmol) and acetonitrile (20 ml) is stirred at reflux for 40 hours. Evaporate the solvent. Dichloromethane (50 ml) is added and the mixture is washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase is purified by chromatography on silica gel and a mixture of methanol (10%) and dichloromethane as eluent. The product is isolated as the free base. Yield 0.40 g,
49%. 45-47 ° C. 1- (5-chloro-2-methoxyphenyl) -3- (3- (trifluoromethyl
)) Phenyl) guanidine (Compound 3c) is prepared according to Method E. Melting point 9
4-96 ° C. 1,3-bis (3- (trifluoromethyl) phenyl) guanidine (compound 3d
) Is prepared according to Method E. 108-110 ° C. 3- Cyanamide benzotrifluoride A mixture of 3-aminobenzotrifluoride (15.0 g, 93.1 mmol), cyanogen bromide (12.2 g, 129 mmol) and diethyl ether is stirred under reflux for 40 hours. The crude mixture is purified by chromatography using silica gel and a mixture of petroleum ether and dichloromethane (1: 1) as eluent.
The product is isolated as the free base. Yield 5.2 g, 25%.

Method F 1- (4-chlorobenzyl) -3- (3-trifluoromethylphenyl) guani
Gin (Compound 3b) 3-Cyanamidobenzotrifluoride (1.20 g, 6.45 mmol)
And a mixture of 4-chlorobenzylamine hydrochloride (1.26 g, 7.09 mmol) at 150 ° C. for 40 hours. Dichloromethane (100 ml) is added and the mixture is washed with saturated aqueous sodium hydrogen carbonate solution (100 ml). The organic phase is purified by chromatography on silica gel and a mixture of methanol (10%) and dichloromethane as eluent. The product is isolated as the free base.
Yield 1.05 g, 50%. 103-105 ° C. 1- (2-bromo) -5- (trifluoromethyl) phenyl) -3- (3-tri
Fluoromethyl) phenyl) guanidine (Compound 3e)
Manufacture at 30 ° C. for 15 hours. It is isolated as an oil. 5-chloro-1,3-bis (4-chlorobenzyl) -2-iminobenzimidazo
Phosphorus (compound 4a) 2-amino-5-chloro-benzimidazole (9.4 g, 56.1 mmol)
), 4-chlorobenzyl chloride (9.93 g, 61.7 mmol), potassium carbonate (15.5 g, 112 mmol) and dimethylformamide (150 ml)
)) Is stirred at 50 ° C. for 20 hours. Water (150 ml) is added and the product is filtered. The crude product is purified by chromatography on silica gel and a mixture of ethanol (5%) and dichloromethane as eluent. The product is isolated as the free base. Yield 0.37 g, 2%. Melting point 175-177 [deg.] C. To a mixture of 2-amino-5-chlorobenzimidazole 2-amino-4-chloroaniline (15.2 g, 106.6 mmol) and dimethylformamide (150 ml) was added cyanogen bromide (14.7 g, 13
8.6 mmol) are added. The mixture is stirred for 3 days. Water (300 ml) is added and small impurities are removed by filtration. Sodium hydroxide (212 ml,
2M) is added to the filtrate and the mixture is extracted five times with ethyl acetate (50 ml). The organic phase is washed with sodium hydroxide (100 ml, 4M), dried and evaporated to dryness.
The residue is finally triturated with petroleum ether, leaving the product. Yield 9.4 g,
53%. Method B using 2 -amino-4-chloroaniline from 4-chloro-2 -nitroaniline
It is manufactured according to.

Method G2-chloro-5- (6-amino-5,6,7,12-tetrahydrodibenzo [d
, G] [1.3.6] triazocin-12-yl) benzonitrile (Compound 4b
) N, N-bis (2-aminophenyl) -3-chloro-4-cyanoaniline (2
. 6 g, 7.76 mmol), cyanogen bromide (2.46 g, 23.3 mmol) and
And a mixture of dimethylformamide (30 ml) is stirred at room temperature for 5 days. Water (1
00 ml) and the aqueous phase is washed with diethyl ether (100 ml). Water phase
To the mixture was added sodium hydroxide (1M, 100 ml) and the mixture was twice ethyl acetate (
100 ml). The crude extract was silica gel and ethanol (eluent)
10%) and purified by chromatography using a mixture of dichloromethane
I do. The product is isolated as the free base. Yield 0.50 g, 28%. Melting point 225
-228 ° C.5,6,7,12-tetrahydrodibenzo [d, g] [1.3.6] triazosi
N-6-imine (Compound 4d) is prepared according to Method G. Melting point decomposition.N, N-bis (2-aminophenyl) -3-chloro-4-cyanoaniline Hydrochloride N, N-bis (2-nitrophenyl) -3-chloro-4-cyanoaniline, charcoal
Palladium (0.70 g, 5%) supported on silicon and ethanol (100 ml
) Is stirred under hydrogen until 2.5 L is consumed. Celite pad with reaction mixture
And add hydrogen chloride in methanol (4M, 30 ml) and remove the solvent.
Remove by evaporation. The residue is triturated with ethyl acetate, leaving a crystalline product
I do. Yield 3.8 g, 53%. Melting point 184-187 [deg.] C.N, N-bis (2-nitrophenyl) -3-chloro-4-cyanoaniline 3-chloro-4-cyano-aniline (40.0 g, 262 mmol),
Fluoro-2-nitrobenzene (40.7 g, 288 mmol) and potassium carbonate
(36.2 g, 262 mmol) in water attached to a condenser
Stir at 180 ° C. overnight using a collector. Add water (300 ml) and add
Extract with chill ether. Chromatography using dichloromethane with the product as eluent
Isolated by chromatography. Yield 7.3 g, 7%. 165-167 ° C. 1- (2-aminophenyl) -2-imino-3-phenyl-imidazoline Hydrochloride
(Compound 4c) was converted to 2-imino-1- (2-nitrophenyl) -3-phenyl-i
Prepared from midazolidine by Method B. 228-230 ° C.2-imino-1- (2-nitrophenyl) -3-phenyl-imidazolidine To N
Process A from -phenyl-N '-(2-nitrophenyl) ethylenediamine
To manufacture. 257-259 ° C.N-phenyl-N '-(2-nitrophenyl) ethylenediamine 1-fluoro-2-nitrobenzene (15.5 g, 110 mmol) and carbonic acid
A mixture of sodium (15.2 g, 110 mmol) was treated with N-methylpyrrolidone (
20 ml) and N-phenylethylenediamine (15.0 g, 110 mmol)
Is added over 1 hour at room temperature. The mixture is stirred for one hour. Water (200
ml) are added and the crystals are filtered and triturated with petroleum ether. Yield 14.7g
, 52%. 64-66 [deg.] C.

Example 18

[0181]

Embedded image Cis-1,5-bis (2-amino-1-benzimidazolyl) cyclooctane (
Compound 1j) 2-aminobenzimidazole (0.22 g, 1.6 ) in DMF (25 ml).
Sodium hydride (70 mg, 6 mg).
(0% mineral oil dispersion) and the mixture is stirred for 30 minutes before the addition of cis-1,5-bis (p-toluenesulfonyloxy) cyclooctane. The resulting mixture is stirred at 100 ° C. for 4 days, cooled and filtered. The filtrate is diluted with water, the precipitate is filtered, washed with water and dried to give the desired product (9mg).

Example 19 Biological Activity This example demonstrates the biological activity of the compounds of the present invention. Compound 1 of Example 3
A and IF, compound 1B of example 2, compound 1J of example 19 and compound 7F of example 11 are investigated.

In this experiment, a small conductance Ca ²⁺ activated K ⁺ channel (SK
The channel, isoform 2), which has been cloned from a rat cDNA library, is stably expressed in HEK293 cells using standard procedures. The ion current passing through the channel is recorded by the whole-cell mode of the patch clamp method.

The cells applied on the coverslips were transferred to Nomarski or Hoffmann.
Place in a 15 μL perfusion box (flow rate １1 ml / min) equipped with an IMT-2 microscope with optics. Place the microscope on a vibration-free table in the basal Faraday cage.

All experiments are performed at room temperature (20-22 ° C.). EPC-9 patch clamp amplifier (HEKA-electronics, Lambrect, Germany)
Connect to Macintosh computer via 16 interface. The data is stored directly on the hard disk and analyzed by IGOR software according to the manufacturer's instructions.

The whole cell configuration of the patch clamp method is applied. Briefly, the tip of a borosilicate pipette (resistance 2-4 MΩ) is gently placed on the cell membrane (remote control system). Light aspiration occurs at the giga seal (pipette resistance increases to 1 GΩ or more), and the cell membrane is then ruptured with stronger aspiration. The cell capacitance is electronically compensated and the pipette and cell interior (series resistance, Rs) are measured and compensated. Normally, cell capacitance ranges from 5 to 20 pF (depending on cell size), and series resistance is in the range of 3-6 MΩ. Rs-compensation and capacitance compensation are updated during the experiment (before each stimulus). All experiments with drift of the Rs value are performed. There is no leak-substractions.

Solution The extracellular (bath) solution was 144 KCl, ₂ CaCl ₂ , MgCl ₂ , 10 HEPE.
S (pH = 7.4) (concentration mM).

[0188] The test compound is dissolved as a 1000-fold concentrated stock solution in DMSO and then diluted in extracellular solution.

In an experiment in which the effect of the channel activator is quantified (test 475), the intracellular (pipette) solution has the following composition (concentration mM): 144 KCl, 10 EDTA, 1.4 MgCl ₂ , 5.17 CaCl ₂ And 10
HEPES (pH = 7.2).

The calculated free concentration of Ca ^{2+ in} this solution was 100 nM, and the concentration of Mg ²⁺ was 1 m
M. In these experiments, the concentration of CaCl ₂ was 7.6 mM and the concentration of MgCl ₂ was 1.2 mM, yielding calculated free concentrations of 300 nM and 1 mM, respectively.

[0191] After the adjustment of the configuration of quantify whole cell voltage ramp (usually - 100 to + 100 mV) 5
Apply to cells every second. A stable reference current is obtained for 100-300 seconds, then the compound is added by changing to an extracellular solution containing the compound to be tested. Few endogenous currents (<2 at 100 mA compared to 2-20 nASK currents)
00pA) is activated under these conditions in native HEK293 cells.

The IC ₅₀ value is calculated from the kinetics of the block. The time course for the decrease in current conforms to the following equation: I = _IO ^* (1- (C / C + ( _Koff / _Kon ))) ^* (1-exp (-(C ^* _Kon + _Koff). ) ^* T))) (where K _off = off rate (s ⁻¹ ) K _on = on rate (M ⁻¹ s ⁻¹ ) I _O = basic current (nA) C = drug concentration (μM) IC ₅₀ Is equal to the ratio K _off / K _on .) All of the compounds of the invention tested in this experiment have a biological activity measured as an IC _{50 in the} submicromolar and lower micromolar range, ie about 1 μM.
約 about 10 μM (below 1 to above 10 μM).

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] May 27, 2000 (2000.5.27)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claim 1

[Correction method] Change

[Correction contents]

Embedded image (In the formula, A represents a space group having 1 to 20 atoms, provided that A is CH ₂ -phenyl-CH ₂ , CH ₂ OCH ₂ , (CH ₂ ) _3-5 , N = N or (CH ₂ ) A compound represented by the formula:

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] Claim 2

[Correction method] Change

[Correction contents]

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] Claim 3

[Correction method] Change

[Correction contents]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] Claim 4

[Correction method] Change

[Correction contents]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/435 A61K 31/435 4H006 31/473 31/473 31/496 31/496 31/506 31/506 31/5377 31/5377 A61P 1/00 A61P 1/00 3/10 3/10 9/00 9/00 9/06 9/06 9/12 9/12 11/00 11/00 11/06 11/06 13/00 13/00 13/12 13/12 15/06 15/06 17/14 17/14 21/04 21/04 25/00 25/00 25/06 25/06 25/08 25/08 25 / 18 25/18 25/22 25/22 25/24 25/24 25/28 25/28 35/00 35/00 37/06 37/06 43/00 43/00 111 111 C07D 219/08 C07D 219/08 235/20 235/20 235/30 235/30 B 239/42 239/42 Z 403/10 403/10 417/04 417/04 417/12 417/12 487/18 487/18 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA , CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI , SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Strebeek-Dorte, Denmark, 2750 Valerup, Peder Strupbey 93, Neurosir Ach Aktizerskab・ Aktiselskab (72) Inventor Peters Dan Denmark, 2750 Barelup, Pederstorpbay 93, Neurosar Achi Aktiselskab F-term (reference) 4C034 BD20 4C050 AA02 AA07 BB05 CC12 EE04 FF05 GG01 HH01 4C063 AA01 BB01 CC26 CC62 DD22 DD26 EE01 4C086 AA01 AA03 BC39 BC42 BC50 BC58 BC73 BC82 DA25 GA07 GA09 GA10 GA12 MA01 MA04 NA14 ZA08 ZA12 ZA15 ZA16 ZA18 ZA34 ZA36 ZA38 ZA40 ZA42 ZA59 ZA66 ZA81 ZA92 ZB02 ZB09 A02 ZA12 ZA15 ZA16 ZA18 ZA34 ZA36 ZA38 ZA40 ZA42 ZA59 ZA66 ZA81 ZA92 ZB02 ZB08 ZB26 ZC02 ZC35 ZC41 4H 006 AA01 AB20

Claims (34)

[Claims] 1. A compound of the formula I (In the formula, A represents a space group having 1 to 20 atoms.) 2. The method according to claim 1, wherein the space group A is a linear or branched alkylene chain having from 1 to 15 carbon atoms, the alkylene group being represented by one or more oxygen or sulfur atoms or of the formula --NR '- or = NR' (wherein, R 'represents hydrogen or alkyl.), or a ─── may be interrupted represented residues by one or more elements, or in the formula - (CH _{2 ) a -D- (CH 2) b} - ( wherein, a and b may be the identical or different, represents the number of 0, 1, 2, 3, or 5, D is a carbon atom 6-1
2. A compound as claimed in claim 1, which is a di-residue represented by a cycloalkyl or aryl group having two, wherein said aryl group may in particular be a phenyl or biphenyl group. 3. A is decamethylene, octamethylene, hexamethylene, pentamethylene, tetramethylene, trimethylene, dimethylene, N, N'-dimethyl-diamino-methylene, N, N'-dimethyl-diamino-dimethylene, N, N '
-Dimethyl-diamino-trimethylene, (cis and / or trans) -1,5
-Cyclooctylene, (cis and / or trans) -1,3-dimethylcyclohexane-α, α′-diyl, para-xylene-α, α′-diyl, meta-xylene-α, α′-diyl, 1,3-phenylene, biphenyl-3,3′-diyl, 4,4′-dimethyl-bibenzyl-α, α′-diyl, 4,4′-dimethyl-
Diphenylmethane-α, α′-diyl, 4,4′-dimethyl-cis and / or
Trans-stilbene-α, α′-diyl, 2,6-bis (4′-methyl-phenyl) pyridine-α, α′-diyl, 3,3′-dimethyl-biphenyl-α, α
The compound according to claim 2, which is' -diyl or 2,7-dimethyl-9H-fluorene-α, α'-diyl. 4. A 1,3-bis [(2-aminobenzimidazol-1-yl) methyl] cyclohexane, 1,6-bis (2-aminobenzimidazol-1-yl) hexane, 1,4-bis ( 2-aminobenzimidazol-1-yl) butane, 1,3-bis (2-aminobenzimidazol-1-yl) propane, 1,2-bis (2-aminobenzimidazol-1-yl) ethane, α, α′-bis (2-aminobenzimidazol-1-yl) -para-xylene, α, α′-bis (2-aminobenzimidazol-1-yl) -meta-xylene, 1,3-bis (2- Aminobenzimidazol-1-yl) benzene, 3,3'-bis (2-aminobenzimidazol-1-yl) biphenyl or cis and / or trans-1,5-bis ( - amino benzimidazole -1
-Yl) cyclooctane. 5. A compound of the general formula II Wherein R ¹ is a mono- or polycyclic aryl group, an aralkyl group, a mono- or polycyclic heterocyclic group. The aryl group, aralkyl group and heterocyclic group may be halogen, alkyl, alkoxy, , Alkoxyalkyl, cyano, trifluoromethyl, phenyl, guanidino (this guanidino may be optionally substituted by alkyl, phenyl or benzyl), primary, secondary or tertiary amino groups, ie alkyl groups optionally substituted one or more times by one or two times substituted amino group (-NH _2, -NH- alkyl and -N (alkyl) ₂₎ substituent selected from the group consisting of the ── ──, or the single - or bind to polycyclic heterocyclic group, a monocyclic or polycyclic ants Lumpur groups described above, R ² is hydrogen, alkyl Or an CF _3. ] The compound represented by these. 6. The compound according to claim 5, wherein R ¹ is phenyl, benzyl, pyrazolyl, imidazolyl, thiazolyl or isothiazolyl. 7. 2-amino-1- [4- (4-chlorophenyl) -2-thiazolyl] benzimidazole, 2-amino-1- (4-dimethylaminobenzyl) -5-trifluoromethylbenzimidazole, 2 -Amino-1- (4-phenyl-2-thiazolyl) benzimidazole, 2-amino-1- [3- (1,3,5-trimethylpyrazol-4-yl) phenyl] benzimidazole, 2-amino-1 -(4- (N- (2-thiazolyl) amino) phenyl) benzimidazole, 1- (4- (2-aminobenzimidazol-1-yl) phenyl) -3-phenylguanidine 2-amino-1- (4 -Acetamidophenyl) benzimidazole or 2-amino-1- (4-aminophenyl) -benzimidazole. Compound of the mounting. 8. A compound of the general formula III (Wherein R ¹ and R ² may be the same or different and represent hydrogen, alkyl, mono- or polycyclic heterocyclic group, mono- or polycyclic aryl group, aralkyl group, The group, aryl or aralkyl group is optionally halogen, alkyl, alkoxy, alkoxyalkyl, cyano, trifluoromethyl, phenyl, guanidino, which may be optionally substituted by alkyl, phenyl or benzyl. It may be substituted one or more times by a substituent selected from the group consisting of primary, secondary or tertiary amino groups.)
A compound represented by the formula: 9. R ¹ and R ² are furanyl, imidazolyl, isothiazolyl,
Isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, 9. The compound of claim 8, which is thiazolyl, thienyl, benzimidazolyl, indolyl, isoquinolyl, quinolyl, acridinyl, phenazinyl, phenathiadinyl, phenyl, naphthyl, anthracenyl, or benzyl. 10. 1- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (3- (trifluoromethyl) phenyl) guanidine, 1- (4-chlorobenzyl) -3- (3- Trifluoromethylphenyl) guanidine, 1- (5-chloro-2-methoxyphenyl) -3- (3- (trifluoromethyl) phenyl) guanidine, 1,3-bis (3- (trifluoromethyl) phenyl) guanidine 1- (2-bromo-5- (trifluoromethyl) phenyl) -3- (5- (trifluoromethyl) phenyl) guanidine, 1- (4-aminophenyl) guanidine, α, α'-bis (3 The compound according to claim 8, which is -phenylguanidin-1-yl) -para-xylene or 6-amino-3-guanidinoacridine. 11. A compound of the general formula IV Wherein R ¹ and R ² may be the same or different and represent hydrogen, a mono- or polycyclic aryl group or an aralkyl group, wherein the aryl group and the aralkyl group are optionally halogen, alkyl, alkoxy, alkoxyalkyl, cyano, trifluoromethyl, primary, secondary or tertiary amino group, i.e. once or twice substituted amino group I by the alkyl group (-NH _2, -NH- alkyl and -N ( Alkyl) ₂ ) may be substituted one or more times by a substituent selected from the group consisting of: and R ³ is a divalent mono- or polycyclic heterocyclic group, a divalent mono- or polycyclic Aryl group, divalent aralkyl group; the heterocyclic group, the aryl group and the aralkyl group may be halogen, alkyl, alkoxy, alkoxyalkyl, cyano, Trifluoromethyl, primary, secondary or tertiary amino group (the secondary or tertiary amino group may be substituted (once or twice) by an alkyl group or a phenyl group; May be substituted one or more times by a substituent selected from the group consisting of halogen, trifluoromethyl, and / or cyano.) One or more times by a substituent selected from the group consisting of And a divalent residue represented by the formula-(CH ₂ ) _C- (where c is a number of 1, 2, 3, 4 or 5). Or a divalent bridging group bonded to the other mono- or polycyclic aryl group mentioned above and optionally via oxygen, sulfur or nitrogen (in this bridging group, the nitrogen atom is In order to form an amino group, the above mono- or polycyclic aryl It may be additionally substituted by groups.) To form a represents a single or polycyclic aryl groups described above. Compound represented by｝. 12. The compound according to claim 11, wherein R ¹ and R ² represent phenyl or benzyl, which may be optionally substituted one or more times by halogen and / or a primary amino group. . 13. A divalent phenyl group 2 wherein R ³ represents one divalent phenyl group or is bridged by a nitrogen atom to form a secondary or tertiary amino group.
12. The compound according to claim 11, wherein the tertiary amino group is preferably further substituted by a phenyl group, which phenyl group may be optionally substituted by halogen, trifluoromethyl or cyano. . 14. A mixture of 5-chloro-1,3-bis- (4-chlorobenzyl) -2-iminobenzimidazoline and 12- (3-chloro-4-cyanophenyl) -6-imino-5,7,12. -Triaza-di-benzo [a, f] cyclooctane, 1- (2-aminophenyl) -2-imino-3-phenyl-imidazolidine or 6-imino-5,7,12-triaza-di-benzo [ a, f] cyclooctane. 15. A general formula VR-R-R (V) wherein L is a space group having 1-20 atoms, and R is a mono- or polycyclic aryl group, an aralkyl group or Or more
Or a polycyclic heterocyclic group (the heterocyclic group preferably has one or more nitrogen atoms as a hetero atom) or a mono- or polycyclic aryl group or an aryl group bonded to the heterocyclic group as described above. Show. ) The compound represented by these. 16. A linear or branched alkylene chain wherein L has 2 to 5 carbon atoms,
Formula-(CH ₂ ) _a -D- (CH ₂ ) _b- (where a and b may be the same or different, and represent a number of 0, 1, 2, 3, 4, or 5) , D is a carbon atom 6-1
A di-residue or a mono- or polycyclic heterocyclic group represented by a cycloalkyl or aryl group having two (the aryl group may be particularly a phenyl group or a biphenyl group). The compound according to claim 15, wherein the heterocyclic group preferably has one or more nitrogen atoms as a hetero atom. 17. The compound according to claim 16, wherein L represents phenyl, pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl and piperazinyl. 18. A nitrogen-containing heterocyclic ring bonded to a nitrogen-containing heteroaromatic ring (heteroaryl), wherein the nitrogen-containing heterocyclic ring is preferably piperazinyl, and the nitrogen-containing heteroaryl is pyrimidinyl. Or a nitrogen-containing heteroaromatic ring (heteroaryl) (where the nitrogen-containing heterocyclic ring is preferably benzimidazole bonded to an aralkyl group, and the aralkyl group is preferably benzyl). The compound according to claim 15, which shows 19. An α, α′-bis (1- (2-pyrimidyl) piperazin-4-yl) -para-xylene, α, α′-bis ((1- (2-pyrimidyl) -4-methylpipe) Radinium-4-
The compound according to claim 15, which is yl) -para-xylene or 1,4-bis (1-benzylbenzimidazol-2-yl) piperazine. 20. The general formula VI Wherein R ¹ , R ² and R ⁴ may be the same or different and are hydrogen, alkyl, phenyl or benzyl, which phenyl or benzyl optionally comprises halogen, trifluoromethyl and cyano May be substituted one or more times with a substituent selected from the group and R ³ is hydrogen, halogen, trifluoromethyl, cyano, alkyl, phenyl or benzyl.) . 21. 1- (4'-chlorobenzyl) -2-dimethylamino) -5
21. The compound according to claim 20, which is trifluoromethylbenzimidazoline. 22. A compound of the general formula VII Wherein A is a space group having the meaning described for group A in formula I above, and X is hydrogen, halogen, trifluoromethyl, cyano, alkoxy, alkoxyalkyl, alkyl, phenyl or benzyl The phenyl or benzyl may be optionally substituted one or more times with a substituent selected from the group consisting of halogen, trifluoromethyl and alkyl, or a mono- or polycyclic heterocyclic group (this heterocyclic group). The cyclic group preferably has one or more nitrogen, oxygen or sulfur atoms as heteroatoms), which optionally comprises halogen, trifluoromethyl, alkoxy, alkoxyalkyl or alkyl. One or more times substituted by a substituent selected from the group Compounds represented by good.). 23. A is decamethylene, octamethylene, hexamethylene, pentamethylene, tetramethylene, trimethylene, dimethylene, N, N'-dimethyl-diamino-methylene, N, N'-dimethyl-diamino-dimethylene, N, N '
-Dimethyl-diamino-trimethylene, (cis and / or trans) -1,5
-Cyclooctylene, (cis and / or trans) -1,3-dimethylcyclohexane-α, α′-diyl, para-xylene-α, α′-diyl, meta-xylene-α, α′-diyl, 1,3-phenylene, biphenyl-3,3′-diyl, 4,4′-dimethyl-bibenzyl-α, α′-diyl, 4,4′-dimethyl-
Diphenylmethane-α, α′-diyl, 4,4′-dimethyl-cis and / or
Trans-stilbene-α, α′-diyl, 2,6-bis (4′-methyl-phenyl) pyridine-α, α′-diyl, 3,3′-dimethyl-biphenyl-α, α
23. The compound of claim 22, which is' -diyl or 2,7-dimethyl-9H-fluorene-α, α'-diyl. 24. cis / trans-1,4-bis [(2-chlorobenzimidazol-1-yl)
Methyl] cyclohexane, cis / trans-1,4-bis [2- (1-pyrrolidinyl) benzimidazol-1-yl) methyl] cyclohexane, cis / trans-1,4-bis [2- (4-morpholinyl) benz Imidazol-1-yl) methyl] cyclohexane, cis / trans-1,4-bis [2- (1-methylpiperazin-4-yl) benzimidazol-1-yl) methyl] cyclohexane or α, α′-bis ( 23. The compound of claim 22, which is 1-benzimidazolyl) -meta-xylene. 25. A compound of the general formula VIII Wherein A and B may be the same or different and represent a space group having 1-20 atoms, X is as described in formula VII above, Y is a halide , Preferably chlorine, bromine or iodine.) 26. A and B are linear or branched alkylene chains having from 1 to 15 carbon atoms, the alkylene radicals having one or more oxygen or sulfur atoms or of the formula --NR '- or = NR' (wherein, R 'represents hydrogen or alkyl.), or a ─── may be interrupted represented residues by one or more elements, or in the formula - (CH _{2 ) a -D- (CH 2) b} - ( wherein, a and b may be the identical or different, represents the number of 0, 1, 2, 3, or 5, D is a carbon atom 6-1
A cycloalkyl or aryl group having two (the aryl group may in particular be a phenyl or biphenyl group) is indicated. 26. The compound according to claim 25, which represents a di-residue represented by: 27. A and B independently of one another are decamethylene, octamethylene,
Hexamethylene, pentamethylene, tetramethylene, trimethylene, dimethylene, N, N'-dimethyl-diamino-methylene, N, N'-dimethyl-diamino-
Dimethylene, N, N'-dimethyl-diamino-trimethylene, (cis and / or trans) -1,5-cyclooctylene, (cis and / or trans) -1
, 3-Dimethylcyclohexane-α, α'-diyl, para-xylene-α, α '
-Diyl, meta-xylene-α, α′-diyl, 1,3-phenylene, biphenyl-3,3′-diyl, 4,4′-dimethyl-bibenzyl-α, α′-diyl,
4,4′-dimethyl-diphenylmethane-α, α′-diyl, 4,4′-dimethyl-cis and / or trans-stilbene-α, α′-diyl, 2,6-bis (4′-methyl -Phenyl) pyridine-α, α′-diyl, 3,3′-dimethyl-biphenyl-α, α′-diyl or 2,7-dimethyl-9H-fluorene-
27. The compound according to claim 26, which is [alpha], [alpha] '-diyl. (28) 1,1 '-(α, α'-para-xylylene) -3,3'-(α
, Α'-meta-xylylene) -bis (benzimidazolium).
5. The compound according to 5. 29. The compound according to claim 1, which is used as a medicament. 30. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-28. 31. A method for using a compound according to any one of claims 1 to 28 for producing a medicament for treating or reducing a disease or disorder associated with potassium channel activity. 32. The disease or disorder is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vasospasm, coronary artery convulsions, renal dysfunction, renal polycystic disease, bladder convulsions, urinary incontinence, bladder Outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, intracerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, traumatic encephalopathy, mental illness, anxiety, depression , Dementia, memory and attention deficit, Alzheimer's disease,
Dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome,
32. The use according to claim 31, wherein the use is migraine, arrhythmia, hypertension, apsance attack, myotonic muscular dystrophy, xerostomia, diabetes type II, hyperinsulinemia, premature birth, baldness, cancer and immunosuppression. 33. A method for treating or alleviating a disorder or disease in living organisms including humans, wherein the disorder or disease is responsive to blockage of potassium channels. A method according to any of the preceding claims, wherein a therapeutically effective amount of any of the compounds is administered to an animal body, including a human, in need thereof. 34. The disease or disorder is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsion, vasospasm, coronary artery convulsion, renal disorder, renal polycystic disease, bladder convulsion, urinary incontinence, bladder Outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, intracerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, traumatic encephalopathy, mental illness, anxiety, depression , Dementia, memory and attention deficit, Alzheimer's disease,
Dysmenorrhea, narcolepsy, Raynaud's disease, intermittent claudication, Sjogren's syndrome,
34. The method of claim 33, wherein the method is migraine, arrhythmia, hypertension, apsance attack, myotonic muscular dystrophy, xerostomia, diabetes type II, hyperinsulinemia, premature birth, baldness, cancer and immunosuppression.